Ionis Pharmaceuticals (IONS) Stock Drops 20% After Heart Drug Fails Phase 3 Trial

TLDR

• Ionis Pharmaceuticals stock dropped nearly 20% after its Phase 3 CARDIO-TTRansform trial for eplontersen failed to meet its primary endpoint
• Partner AstraZeneca also fell roughly 9% on the news
• The drug showed no benefit in patients already taking a stabilizer medication, which made up the majority of trial participants
• A subgroup of patients not on stabilizers showed a 29% risk reduction, offering a partial positive
• Rival drugmakers Alnylam and BridgeBio surged double digits on the news, as a key competitor appears removed from the ATTR-CM space

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Ionis Pharmaceuticals (IONS) stock dropped around 17-20% on Thursday after the company and partner AstraZeneca (AZN) announced that their Phase 3 CARDIO-TTRansform trial for eplontersen failed to meet its primary endpoint.

Ionis Pharmaceuticals, Inc., IONS

The trial tested whether eplontersen could reduce the risk of heart-related deaths and repeat cardiovascular events in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) compared to a placebo over 140 weeks. It did not.

IONS was trading down roughly 17.59% on Thursday. That extends a year-to-date loss of 11.78%, though the stock is still up about 99% over the past 12 months.

U.S.-listed AstraZeneca stock fell around 9% on the same news, reflecting how much both companies had riding on this outcome.

The trial enrolled a patient population where 57% were already on a stabilizer drug at the start, with another 24% starting one during the study. In that context, eplontersen showed no treatment effect. That’s a problem, because stabilizer use has become the norm in clinical practice.

Where It Did Work — And Why That May Not Be Enough

There was a silver lining. In patients who were not on a stabilizer drug, eplontersen showed a 29% reduction in the combined risk of cardiovascular death and repeat events. The drug also produced strong, sustained reductions in transthyretin protein levels and hit several secondary endpoints.

But analysts weren’t buying the partial win as a path forward. Stifel’s Paul Matteis wrote that “trying to approach regulators here on these data would seem like a stretch.” Neither Ionis nor AstraZeneca announced plans to seek regulatory approval or run a follow-up study.

CEO Brett Monia acknowledged the disappointment, pointing to the shifting treatment landscape where more patients now start on stabilizers before entering trials. The full dataset will be presented at the European Society of Cardiology Congress in August 2026.

For Ionis specifically, the failure cuts off expected profit-sharing, royalties, and future milestone payments tied to eplontersen’s success in heart disease.

Rivals Move Higher as Competition Thins

Alnylam Pharmaceuticals and BridgeBio both jumped double digits on Thursday. With eplontersen’s future in ATTR-CM now in doubt, Alnylam’s Amvuttra looks set to hold its position as the only RNA-silencing therapy in the space.

Stifel’s Matteis called it “a huge positive” for Amvuttra. Pfizer’s Vyndamax, already the market leader with over $6 billion in sales last year, also stands to benefit from one fewer competitor.

Jefferies analyst Michael Leuchten said the bigger issue for AstraZeneca isn’t the revenue miss — it’s the credibility hit. The company had gone into the readout with high confidence. “AstraZeneca is meant to be able to have exceptionally good trial design ability,” he noted.

Wall Street’s consensus on IONS heading into Thursday was Strong Buy, with an average price target of $104.61. Those ratings are likely to be revised.

Trading volume in IONS hit around 3 million shares on Thursday, well above the three-month daily average of 1.86 million.